PROJECT SUMMARY African American (AA) men have a higher rate of metastatic, castration-resistant prostate cancer (CRPC) than other men. However, the genetics contributing to this disparity remain elusive. Our preliminary data show that CD24 is not expressed in normal prostate epithelial cells but is overexpressed in high-stage PC and metastases, especially in AA men. In particular, highly expressed alleles of CD24 genetic variants are more frequently present in AA men than in other groups. Thus, CD24 appears to contribute to metastatic CRPC in AAs. The oncogenic function of CD24 has been demonstrated by ectopic and/or inducible expression, targeted mutations, gene silencing, and antibody blockade. Notably, we developed a new concept of CD24- dependent inactivation of mutant p53 in PC cells. Since mutant p53 is frequently associated with metastatic CRPC, we hypothesize that CD24 promotes mutant p53 inactivation that contributes to tumor metastasis in AA CRPC patients, which will be tested in two specific aims. Aim I will determine the effect of CD24- dependent inactivation of mutant p53 on tumor metastasis in CRPC cells. Aim II will characterize the association between CD24, mutant p53, and tumor metastasis in AA CRPC patients. Our proposed work will provide a better understanding of the molecular mechanisms of the aggressive pathogenesis of PCs in AA men and can be used to benefit AA men at risk of developing aggressive CRPCs.